SCD Children Research Articles

Diagnostic Potential of Platelet-Neutrophil Ratio (PNR) for Stroke Risk in SCD Children

Diagnostic Potential of Platelet-Neutrophil Ratio (PNR) for Stroke Risk in SCD Children

Factors associated with adverse outcome among children with sickle cell disease admitted to the pediatric intensive care unit: an observational cohort

BackgroundSickle cell disease (SCD) is one of the most frequent inherited diseases in the world. Over the last decades, in high-income countries, an important decrease in mortality have been observed due to the improvement of care. However, children with SCD can become critically ill and require admission in Pediatric Intensive Care Units (PICU). The purpose of this study was to describe the epidemiology of children with SCD admitted to PICU for acute crisis and to identify factors associated with adverse outcome (AO).MethodsWe conducted a retrospective study in a Tertiary Hospital in France including all consecutive children with SCD admitted to PICU between January 1st, 2009 and December 31, 2019. We collected baseline patient’s characteristics, clinical and biological data as well as treatments and life sustaining therapies used in the PICU. Patients were defined as experiencing AO in case of death during stay and/or need for invasive mechanical ventilation (MV) and/or for non-invasive ventilation (NIV) for more than 3 days and/or need for vasopressors and/or need for renal replacement therapy.ResultsWe included 579 admissions in 395 patients, mainly of SS genotype (90%) with a median age of 9.2 years [5.5–13.4] and a median baseline hemoglobin of 8.0 g/dl (7.5–8.8). The two main reasons for admission were acute chest syndrome (ACS) (n = 331, 57%) and vaso-occlusive crisis refractory to first line therapy (n = 99, 17%). Half of patients required NIV and 47 (8%) required MV. The overall length of stay was 3 days [1–4] and seven (1%) patients died during PICU stay.There was a total of 113 (20%) admissions with AO and on multivariable analysis, baseline hemoglobin < 8 g/dL, history of bronchial obstruction and admission for ACS were associated with AO. There was no difference in the proportion of hydroxyurea treatment or exchange transfusion program between patients with AO and the other patients.ConclusionsBaseline hemoglobin < 8 g/dL, history of bronchial obstruction and admission for ACS were the strongest risk factors for severe evolution in SCD children admitted to PICU. These factors could be taken into consideration when choosing the adequate therapeutic options.

Minor physical anomalies including palatal rugae pattern and palatal dimensions in children with sickle cell disease: A cross-sectional analytical study

BackgroundSickle cell disease (SCD) is the most common hereditary hemoglobinopathy, which delays growth leading to an altered skeleton and craniofacial pattern. Palatal rugae patterning has been considered the regulator of the development of the palate. The purpose of the research work was to study the morphology of the palate, rugae pattern, and its dimensions in SCD children and compare them with healthy normal children, and to evaluate its role as minor physical anomalies (MPAs). MethodsA cross-sectional case-control study was designed as per STROBE guidelines. The sample comprised 50 children diagnosed with sickle cell disease (Group SCD) and 50 normal healthy children as control (Group C) belonging to the same age group (10–18 years). Dental impressions were made, followed by the pouring of dental casts. The length of the palatal rugae was measured and categorized into primary (>5 mm), secondary (3 mm–5 mm), and fragmentary rugae (<3 mm). The shape of each primary palatal rugae was identified and categorized as curved, wavy, straight, circular and non-specific. Linear and angular measurements of the palatal rugae patterns and palatal dimensions (width, height, area) were measured and recorded. ResultsThe total number of palatal rugae and fragmentary rugae was lesser in Group SCD than in Group C (p < 0.05). The depth of the palate was significantly increased, whereas the area of the palate significantly decreased in Group SCD. ConclusionsThe children with SCD showed distinctive palatal rugae patterns and dimensions when compared with normal healthy children that can be attributed as potential MPAs for sickle cell disease. Children with SCD had an under-developed palatal rugae pattern with a deep, narrow and small palate when compared to healthy children.The dimensions of the palatal rugae pattern in SCD showed reduced distance between the incisive papilla and the first and last rugae, indicating a further decrease in the anteroposterior dimensions of the palate. These findings may aid in the early diagnosis and prevention of malocclusion in children with SCD by appropriate interceptive orthodontic treatment

Positive Impacts of the Universal Newborn Screening Program on the Outcome of Children with Sickle Cell Disease in the Province of Quebec: A Retrospective Cohort Study

Background Sickle cell disease (SCD) is the most common monogenic disease worldwide. Benefits of preventive measures such as early penicillin prophylaxis and ease of neonatal diagnosis led to the inclusion of SCD in newborn screening programs (NSP) in the US and later in several Canadian provinces. Universal NSP was implemented in the province of Québec (QcNSP) in November 2013, close in time to the recommendation of early hydroxyurea (HU) therapy. Our study objective was to evaluate how the QcNSP impacted the clinical outcomes of SCD infants and children followed at CHU Ste-Justine between the age of 0-5 years of age. We hypothesized that the introduction of QcNSP has shortened the time to referral to SCD comprehensive centres and the time to HU initiation, while also reducing the number of acute SCD complications. Methodology This is a retrospective cohort study of patients referred to the pediatric comprehensive SCD centre at CHU Sainte-Justine (Montreal), a leading tertiary pediatric center in Canada from Jan 1-2000, to Dec 31-2019. To be included, patients had to be followed for at least two years. Two cohorts were defined: Cohort Pre-QcNSP included patients who had their first visit between January 1 st 2000 and October 31 st2013, whereas cohort post-QcNSP included patients who had their first visit between November 1st 2013 and December 31 st 2019. SCD genotypes were stratified into two groups: HbSS/Sß 0 and SC/Sß +. Reasons for referral were extracted. A Kaplan-Meier curve for hospitalization-free survival (HFS), a poisson regression for the number of VOC emergency (ED) visits and a logistic regression for clinical outcomes, adjusting for age at first visit, gender, place of birth, follow-up period and QcNSP were computed. The software R version 4.2.1 was used for all statistical analyses. The study was approved by the local IRB. Results Of 600 files examined, 410 met the inclusion criteria. 253 were referred pre-QcNSP, 157 post-QcNSP. There were equal gender representations in both groups, and no statistical differences between genotype representation between cohorts. Median age at 1st visit decreased from 1.2 [IQR: 0.2-6.0] pre-QcNSP to 0.2 years [IQR:0.1-4.8] post-QcNSP (p&amp;lt;0.001). The percentage of children born in the province of Qc diagnosed through NS increased from 48.1% (79) pre-QcNSP to 100% (102) post-QcNSP (p&amp;lt;0.004). The percentage of undiagnosed children born in Qc and referred after a first SCD-related complication (DRC) dropped from 42% to 0% (p&amp;lt;0.0001). The median age of HU-introduction for SS patients decreased from 4.5 [IQR:2.6-5.5] pre-QcNSP to 0.75 years [IQR:0.8-1.08] post-QcNSP (p&amp;lt;0.001). Similarly, the percentage of SS patients receiving HU by the age of 2 years old significantly increased from 28.6% preQcNSP to 59.3% post-DN patients (p=0.003). The overall percentage of SS patients eventually receiving HU was nevertheless statistically not different between cohorts (89.7% (61/68) post-QcNSP vs 82.5% (80/97) pre-QcNSP). The number of hospitalizations in HbSS/Sß 0 decreased from 2 hospitalizations/pt-year pre-QcNSP [IQR 1.0-3.0] to 1.0 [IQR: 0.6-1.4] (p&amp;lt;0.001). Hospitalization-free survival (HFS) also improved (257 days post-QcNSP vs. 140 days pre-QcNSP, p&amp;lt;0.001) for HbSS/Sß 0 patients. Similarly, HFS for VOC was significantly longer post-QcNSP (1320 days vs. 573 days, p&amp;lt;0.002). Evaluating ED visits for VOC, HbSS/Sß 0 children referred pre-QcNSP had much greater risk of ED-VOC visits than post-QcNSP (1.44, CI 1.22-1.67); similarly, SS/Sb 0 children referred for DRC vs NS had a higher risk of ED-visit for VOC (0.25, CI 0.02-0.48). There was however no statistical difference in SC/Sß + patients. Conclusion. In Quebec, the universalization of the NSP has enabled early detection and referral of children with SCD to comprehensive care centre. Earlier access to this expertise ensures that children benefit from the essential preventive interventions that are vaccination, prophylactic penicillin, early HU-use as well as caregiver education. These combined interventions may explain in part the improvement in acute events. This cohort study highlights that universal NSP of SCD is an essential public health measure.

Screening for asthma in preschool children with sickle cell disease

Background Asthma in preschool children is poorly defined, proving to be a challenge for early detection. The Breathmobile Case Identification Survey (BCIS) has been shown to be a feasible screening tool in older SCD children and could be effective in younger children. We attempted to validate the BCIS as an asthma screening tool in preschool children with SCD. Methods This is a prospective, single-center study of 50 children aged 2–5 years with SCD. BCIS was administered to all patients and a pulmonologist blinded to the results evaluated patients for asthma. Demographic, clinical, and laboratory data were obtained to assess risk factors for asthma and acute chest syndrome in this population. Results Asthma prevalence (n = 3/50; 6%) was lower than atopic dermatitis (20%) and allergic rhinitis (32%). Sensitivity (100%), specificity (85%), positive predictive value (30%), and negative predictive value (100%) of the BCIS were high. Clinical demographics, atopic dermatitis, allergic rhinitis, asthma, viral respiratory infection, hematology parameters, sickle hemoglobin subtype, tobacco smoke exposure, and hydroxyurea were not different between patients with or without history of ACS, although eosinophil was significantly lower in the ACS group (p = 0.0093). All those with asthma had ACS, known viral respiratory infection resulting in hospitalization (3 RSV and 1 influenza), and HbSS (homozygous Hemoglobin SS) subtype. Conclusion The BCIS is an effective asthma screening tool in preschool children with SCD. Asthma prevalence in young children with SCD is low. Previously known ACS risk factors were not seen, possibly from the beneficial effects of early life initiation of hydroxyurea.

Effect of Low Dose of Hydroxyurea in SCD Children with Arab-Indian phenotype- Local Experience

Effect of Low Dose of Hydroxyurea in SCD Children with Arab-Indian phenotype- Local Experience

Paediatric sickle cell disease at a tertiary hospital in Malawi: a retrospective cross-sectional study

IntroductionSickle cell disease (SCD) remains a major cause of childhood mortality and morbidity in Malawi. However, literature to comprehensively describe the disease in the paediatric population is lacking.MethodsA retrospective review...

Tolerance and humoral immune response to the yellow fever vaccine in sickle cell disease children treated with hydroxyurea: a multicentre prospective study

Sickle Cell Disease (SCD) children are frequent travellers to countries where Yellow Fever (YF) is endemic, but there are no data regarding the safety and immunogenicity of the vaccine in such children treated with hydroxyurea (HU). The main objective of this study was to compare the tolerance and immune response to YF vaccination in SCD children treated or not with HU. SCD Children < 18years attending the international travel clinics of three large paediatric centres and requiring a first YF vaccination were included in a prospective study. Adverse events were collected 2weeks after vaccination. YF vaccine antibody titres were measured approximately 6months after vaccination. Among the 52 SCD children vaccinated against YF, 17 (33%) were treated with HU. Only mild adverse events, mainly fever and local reaction, were observed in the HU group with a similar frequency in the non-HU group (57% and 35%, respectively, p = 0.30). YF antibody titres were measured in 15/17 patients in the HU group and 23/35 patients in the non-HU group after a median of 6.0months (3.5-8.5) following vaccination. The geometric mean of YF antibody titre was similar in both groups. A protective antibody level was observed in 85% of the children in the HU group versus 100% in the non-HU group (p = 0.14), suggesting a lower effectiveness of the vaccine in patients on HU similarly to what has been described in patients on immune suppressive therapy for other vaccines. YF vaccination seems to be safe and efficient in SCD children treated with HU. Considering the potential risk of severe complications in cases of YF while travelling in Africa for those patients, the benefit-to-risk ratio argues for YF vaccination in all SCD children. Control of a protective antibody titre may also be useful to ascertain an adequate response in those treated with HU.

3-Dimensional echocardiographic evaluation of right ventricular function in pediatric sickle cell disease population

Abstract Introduction Sickle cell disease (SCD) is characterized by chronic hemolytic anemia and intermittent vaso-occlusive events associated with cardiac abnormalities. Aim To assess 3 dimensional (3D) echocardiographic of right ventricle (RV) volumes and function in a pediatric SCD population. Methods Eighteen patients with SCD aged 4 to 17 years old (mean age: 8.0±4 years, 56% male, body surface area (BSA) 1.0±0.35) and 18 healthy controls matched for age, gender and BSA were prospectively included and compared. Echocardiograms were performed using a commercially available ultrasound Philipps EPIQ 9 system using matrix X5–1 transducer. 3D indexed RV volumes and ejection fraction (3D- RVEF) were obtained using full volume acquisitions. RV free wall strain, tricuspid S-wave, tricuspid annular plane systolic excursion (TAPSE), indexed cardiac output, systolic pulmonary pressure (sPAP) and hemoglobin were assessed. Data were analyzed with TomtecArena© software (v2.3, Germany). Results Cardiac output was significantly higher in SCD children (4.5 vs 3.6 l/min/m2, p=0.025), as sPAP (24.9 vs 21.9 mmHg, p=0.015), 3D-RV diastolic volume (58.1 vs 47.5 ml/m2, p=0.025) and 3D-RV systolic volume (28.8 vs 21.4 ml/m2, p=0.005). 3D-RVEF and RV free wall strain were significantly lower in SCD compared to control population (respectively 51.9 vs 56.3%, p=0.018; −28.6 vs −32, p=0.017). There were no difference regarding TAPSE and doppler S-wave. Mean hemoglobin in SCD population was 9.6±1.7 g/dl. Conclusions Despite normal RV systolic function parameters, 3D-RVEF and RV free wall strain are lower in children with SCD. Chronic anemia generating volume overload and vaso-occlusive events could explain these findings. 3D sickle cell Funding Acknowledgement Type of funding source: None

Effect of screen time in the clinical outcome of therapy in children with Autism spectrum disorder and social communication disorder

Children of present day are exposed to excessive screen time from a very young age itself. Among the factors which contribute to this is easy accessibility to gadgets, nuclear families with less support for childrearing due to parental preoccupation, etc. Though there are studies addressing the association between screen time and health effects, there isn’t’ any study addressing the effect of screen time on progress of therapy session in children with special needs, especially Autism or social communication disorders. For the present study, we enrolled children between 2-5years with ASD / SCD and assessed their initial problems and improvement post interventions with ATEC scoring. They were questioned about the screen time their children were exposed initially as well as at the end of training duration and were grouped as &lt;1 hour and &gt;1 hour. Following complete assessment using all the required tools, the children were given all the required standardised therapies according to our unit protocol for ASD and SCD, respectively. This includes sessions of Occupational therapy, speech therapy, ABA, etc. for 6 months. The effect of the sessions in the form of improvement in ATEC scores- total and individual domain scores of both ASD and SCD children were correlated with the screen time exposure and assessed for significance. 70 % of the kids with special needs (ASD&amp; SCD) had media exposure &gt;1 hours in the first year itself and were continuing at &gt;2 hour/day. The present study showed that screen time has significant negative influence affecting improvement following therapies in both ASD and SCD. But ASD children seem to be more affected than SCD. ATEC scoring may be used in both ASD and SCD for follow-up assessment. However, this may require a larger sample for further validation. We caution the use of low quality Screen media intervention in therapy sessions or home for engaging these 2 groups of children.

Are Chemokines IL-8 (CXCL8) and MCP-1 (Monocyte Chemoatractant 1) Cooperating to Enhance Inflammation in Children with Sickle Cell Disease Living in Sub-Saharan area?

1. Introduction ickle cell disease is a genetic disease very prevalent in the world and particularly in Sub-Saharan African countries. The prevalence ranges from 20% and 30%. In some African countries, it can reach 45% [1]. The number of newborns affected by this genetic disease is estimated at 240,000 per year or 0.3 to 25 per 1000 live births with fifty to seventy five percentages who do not reach the age of five [2–4]. In Côte d’Ivoire, country located in west Africa, the SCD prevalence rate is 12% [5]. As such, SCD is one of the greatest public health treat of all time and represent a public health problem. This disease makes patients more vulnerable to infections with high mortality, organs damage, and chronic anemia among children [6]. A better comprehension of the disease physiopathology in general will help to develop therapeutic approach to improve the management of the patients. There is an ongoing regular inflammatory status due to high levels of cytokines [7]. In this course, chemokines CXL and CCL also have been identified participating in this inflammatory process, particularly Interleukin-8 (IL8 or CXCL-8) and Monocyte Chemoattractant Protein-1, (MCP-1or CCL2). These two chemokines have been identified as having a chemotactic activity for neutrophils, monocytes, macrophages and lymphocytes [8]. Detection of inflammatory cytokines in the during non-crisis periods could be a guide for medical to improve management of SCD patients. This study strives to observe whether chemokines IL-8 and MCP-1 can be used to predict morbidity or mortality in SCD children.

Adding Azathioprine and Hydroxyurea Preconditioning to Alemtuzumab/TBI May Improve Donor Chimerism in Matched Sibling Donor Allogeneic Stem Cell Transplantation in Adult Sickle Cell Patients

Introduction Sickle cell disease (SCD) is a severe, inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crisis (VOC) and progressive organ damage, resulting in poor quality of life and reduced life expectancy. Improvements in supportive care, use of (exchange) blood transfusions and hydroxyurea have resulted in better survival in SCD children. Nevertheless, SCD related organ damage continues during adult life, resulting in increased morbidity and mortality. Allogeneic stem cell transplantation is currently the only curative treatment option for SCD. In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab + 3 Gy total body irradiation (TBI)) using peripheral blood stem cells has shown promising results in adult SCD patients. In patients treated with this regimen the SCD phenotype resolved with only mild transplantation-related complications, but no reports of graft-versus-host disease (GvHD). However, a large part of these patients did not reach complete donor chimerism and graft failure rates of 8-13% have been reported with this regimen (Hsieh et al. JAMA, 2014; Saraf et al. Biol Blood Marrow Transplant, 2016). Adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism and reduce risk of graft failure. In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI conditioning on donor chimerism and graft failure in patients receiving MSD allogeneic stem cell transplantation for SCD. Methods Adult SCD patients with complications refractory to standard care who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day -10, aiming for HbS &amp;lt;30%. Conditioning with alemtuzumab and TBI was started on day -7, as described by Hsieh et al (N Engl J Med, 2009). GvHD prophylaxis consisted of sirolimus. Data regarding SCD phenotype, donor chimerism and transplantation-related complications were collected prospectively. Results Eight patients (6 HbSS, 2 HbS-β+-thalassemia; median age 29 (range 21 - 49) years; 3 males) have been transplanted as of March 2018. All but one patient reached 100 % donor myeloid chimerism at 1 month. Myeloid chimerism remained stable in those who had reached full donor chimerism at one month (Figure 1A). One patient had 69% donor myeloid chimerism at 1 month, which increased gradually to 90 % at 9 months. Median T-cell donor chimerism at 3 months was 37% (range: 23 - 79%; n=6), increasing further during follow-up (Figure 1B). The percentages of donor myeloid and T-cell chimerism are higher than previously reported with alemtuzumab/TBI only (Hsieh et al. JAMA, 2014). All patients had a corrected SCD phenotype with mostly normalized hemoglobin levels at 3 months (from median 9,5 (IQR 7.8 - 10.7) g/dL at baseline to 12.4 (11.6 - 13.5) g/dL at 3 months, increasing further thereafter. Sirolimus tapering was started at 12 months in the first transplanted patient and stopped without affecting donor chimerism. There were no reports of SCD-related complications. One patient developed acute grade III intestinal GvHD, despite appropriate trough levels of sirolimus, though responded well to high dose steroids. Other treatment-related complications were mTOR inhibitor-associated stomatitis (n=5) responding well to local steroids, arthralgia that was moderately severe in 2 patients and progression of preexistent chronic kidney injury in one patient, which partially recovered after switching sirolimus to mycophenolate mofetil. Conclusion Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI conditioning is well tolerated and may result in improved (higher) donor chimerism after non-myeloablatieve MSD transplantation in SCD patients. Importantly, one patient developed acute GvHD. As (acute) GvHD following alemtuzumab/TBI conditioning has not been reported previously, a relation with the preconditioning (azathioprine) cannot be excluded. Longer term results of larger cohorts are needed to determine the place of azathioprine/hydroxyurea preconditioning in non-myeloablative MSD transplantation for SCD. Disclosures Nur: Novartis Pharmaceuticals: Consultancy. Zeerleder:Jazz Pharma: Speakers Bureau; Sanofi/Genzyme: Speakers Bureau; Alexion: Speakers Bureau.

Hematological Changes from Baseline in Children with Sickle Cell Disease Admitted for Acute Chest Syndrome Compared to Acute Pain Crisis

Title: Hematological Changes from Baseline in Children with Sickle Cell Disease Admitted for Acute Chest Syndrome Compared to Acute Pain CrisisAuthors: Timothy Klouda1, Deepti. Raybagkar2, Bruce Bernstein1, Nataly Apollonsky2,Institutes:1Pediatrics, St Christopher's Hospital for Children, Philadelphia, PA, United States, 2Hematology, St Christopher's Hospital for Children, Philadelphia, PA, United States,Introduction: Children with Sickle Cell Disease suffer from multiple complications including acute pain crisis (VOC) and acute chest syndrome (ACS). Nearly 30% of children with SCD have had one episode of ACS, with the incidence higher in early childhood. The proposed pathophysiology of ACS is thought to be multi-factorial, with pulmonary fat embolism or infectious etiology being identified in a large number of patients. Increased sickling due to hypoxemia or pain has been shown to place patients at risk for ACS development., Studies have shown an increase in inflammatory markers including leukocytes and neutrophils, along with a decreased hemoglobin in SCD children who developed ACS, but no studies to date have compared laboratory changes during the acute illness to their baseline values. We hypothesized that children with SCD who are admitted for ACS will have a larger decrease in hemoglobin from baseline and a higher increase in white blood cell count from baseline when compared to those admitted for an acute pain crisis.Methods: Through retrospective chart review of patients with SCD admitted to St.Christopher's Hospital for Children we identified 45 patients with ACS. Laboratory data collected on admission from chart review included SCD genotype, age, BMI, hemoglobin, white blood cell count, absolute neutrophil count, absolute eosinophil count, platelets, reticulocyte count, hemoglobin F, vital signs and medication history. All 45 children had laboratory data collected from an acute pain crisis that occurred during a different admission for comparison. Collected data was compared to baseline laboratory data, collected during routine visit at sickle cell clinic within 1 year of admission. Changes in laboratory data from baseline during admission for ACS were compared to changes during admission for uncomplicated VOC.Results: Children with SCD who were admitted or developed ACS during admission had a larger increase in leukocyte count (6.99 vs 4.18, p=0.027) and neutrophil count (6.3 vs 3.74, p=0.04) from baseline compared to those admitted for VOC alone. Patients with ACS development also had a larger decrease in platelets (-124.74 vs -56.21, p=.047) from baseline when compared to VOC admissions. There was no statistically significant change from baseline labs when comparing hemoglobin (p=0.10), eosinophil count (p=.382), reticulocyte count (p=0.754), AST (p=0.061) and ALT (p=0.082) in the ACS and VOC groups. Children with a history of 2 or more lifetime ACS were more likely to have OSA (p=0.021), 3 or more VOCs in the past year (p=0.002), and a history of splenectomy, but it was not found to be statistically significant (p=0.155)Conclusion: Children with SCD who developed or were admitted with ACS had a significant increase in leukocyte and neutrophil count from baseline, and a decrease in platelets when compared to VOC admissions. There was no significant change from baseline in hemoglobin, reticulocyte and eosinophils detected. Future larger and multi-center prospective studies need to be performed to confirm the various changes identified in hematological markers seen in ACS vs VOC. DisclosuresNo relevant conflicts of interest to declare.

Variability of ciprofloxacin pharmacokinetics in children: impact on dose range in sickle cell patients.

To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n = 20, 33%), haemopathy (n = 15, 25%), cystic fibrosis (CF; n = 3, 5%) and other diseases (n = 22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean ± SD) was 0.81 ± 0.30 L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.

EVALUTION OF SERUM BETA-2-MICROGLOBULIN AS A MARKER OF RENAL DYSFINCTION IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE

Background: Sickle-cell disease is a multisystem disease, associated with episodes of acute illness and progressive organ damage, and is one of the most common severe monogenic disorders worldwide. Renal dysfunction is a frequent complication in sickle cell disease as a result of long-standing anemia and disturbed circulation through the medullar capillaries, so early detection of it is important to guard against chronic kidney disease. Beta-2-Microglobulin, a low molecular weight protein, is freely filtered in the glomerulus wherefrom it is totally reabsorbed and degraded in the renal tubules. Thus, it is a sensitive marker of the glomerular filtration capacity of the kidney. Objectives: To identify the role of serum Beta-2-Microglobulin as early predictor of renal dysfunction in patients with sickle cell disease. Patients & Methods: We measured serum B-2-Microglobulin in 67 children previously diagnosed as Sickle Cell Disease and attending to Bab Elsharia (Sayed Galal) University Hospital and Misr Children Hospital in period from November 2016 to September 2017. This group of patient was matched with control group (20 children) with the same ages who do not have Sickle Cell Disease and recruited from the same study site. Results: Although, serum B2M was within the reference range, cases had significantly lower serum B2M to the control group. Serum level of B2M was not affected by gender and our data clearly demonstrate age independency for serum concentrations of B2M. Comparing serum B2M to serum creatinine by ROC curve, showed that area under the curve of serum B2M (0.48) versus (0.05) was insignificantly higher and both were below 0.7; indicating that overall predictability of SCD of serum B2M as well as serum creatinine were not statistically significant. Conclusion: ● Renal dysfunction in SCD children may occur before the occurrence of any symptoms or complication. ● Serum B2M is not a good marker in detection of early stages of SCD nephropathy in children. ● A/C ratio and GFR are considerable methods of preliminary detection of glomerular affection in SCD children. Recommendations: ● Routine screening of SCD children with A/C ratio and GFR is mandatory for early detection of renal affection. ● Further studies of establishment of best marker used for early assessment of tubular and glomerular dysfunction in SCD children is recommended.

Otological burdens of Nigerian children with sickle cell disease

Introduction/ObjectiveSickle cell disease (SCD) is associated with episodic illnesses, multi-systemic affectations and end-organs damages. Otolaryngological related complications are not unexpected. Studies on the overall Otolaryngological pathologies in children with SCD relative to their non-SCD counterparts are scanty in Nigeria. We hypothesized that children with SCD are likely to have more otological burdens than their non-SCD counterparts. Thus, we embarked on this study to describe and compare the overall ear diseases burdens seen in children with sickle cell disease relative to their non-SCD counterparts. MethodologyA cross-sectional study of otologic diseases among children with SCD and their non-SCD counterparts attending the paediatrics and otolaryngological clinics of a Nigerian tertiary institution was conducted. ResultsOverall, 80 (47.62%) of the 168 ears of SCD patients compared to 37 (22.02%) of the 168 ears of their non-SCD counterparts were affected by diseases (p < 0.0001). The diseases were Wax, Otitis Media with Effusion, Suppurative Otitis Media, Otosclerosis and Sensorineural Hearing Loss (SNHL). There was a significant difference in the prevalence of SNHL and solitary otosclerosis between the SCD patients and their non-SCD counterparts (P < 0.05) respectively. Both the Haemoglobin concentration and HbF did not discriminate between the SCD participants with or without SNHL (P > 0.05). ConclusionThis study showed that otological burdens are more prevalent in children with SCD than the non-SCD population. The microbiological peculiarity of suppurative otitis media (SOM) among participants stresses the need for concerted efforts at preventing SOM in SCD children. There is need for special Otolaryngological care for SCD children.

Silent Cerebral Infarcts and Retinal changes in patients with Sickle cell Disease

Background: CNS Complications of SCD include headache, seizures, cerebral venous thrombosis, and strokes. 11% and 20% of children with sickle cell anaemia will have overt and silent strokes respectively before their 18th birthday. 14-20% of SCD patients will develop Sickle cell Retinopathy. Aim of study: To look for SCI and Retinal changes in SCD children. Design- Prospective Cross sectional study. Participants- Below 16 yrs in a tertiary care hospital MYH/CNBC Indore, MP. Method: 40 children with SCD &lt; 16 years admitted to Department of Paediatrics, MYH / CNBC Hospital, Indore, from December 2014 to October 2015 were selected and underwent MRI evaluation of brain and fundus examination. Result: Only 6 (15%) had presence of AV tortuosity with dialatation and 4 (10%) had presence of SCI (p&gt;0.05) out of 40. All patients with SCI had presence of AV tortuosity (p=0.001). Statistical Analysis: Kruskal wallis test was applied. Conclusion: 40 children with SCD below the age of 16 years were included, 4(10%) had SCI and 6 (15%) had AV tortuosity and dilatation of retinal vessels. Asymptomatic children of SCD with unanticipated silent infarcts are highly predictive of subsequent clinical stroke and progressive silent infarction. So, these patients should receive frequent blood transfusion to decrease the level of HbS and Hydroxyurea to increase the HbF levels to prevent further subsequent clinical stroke. Also these children should undergo regular ophthalmic checkup for retinal changes and evaluation by MRI Brain for early detection of cerebral infarcts to prevent future occurrence of stroke.

Cognitive Function Of Nigerian Children With Sickle Cell Disease

BackgroundSickle cell disease (SCD) -related neurological complications include overt stroke, silent infarctions and cognitive impairment (CI). CI significantly impacts developmental growth and quality of life. Despite the high prevalence of SCD in sub-Saharan Africa, there is limited information on the burden of neurological dysfunction. To address this gap, we conducted a study to elucidate the prevalence and correlates of CI in SCD-children in an urban tertiary care setting in Nigeria. MethodThis case-control, cross-sectional study was approved by the University of Pittsburgh IRB, Lagos University Teaching Hospital (LUTH) and Lagos State University Teaching Hospital (LASUTH) in Nigeria. Participants were recruited from the LUTH sickle cell clinic and the Sickle Cell Foundation-associated clinics, which included a transcranial Doppler (TCD) clinic. Participants were English-speaking children between the ages 6-16 with laboratory-diagnosed homozygous SCD (HbSS, sickle cell anemia). Children who had an on-going sickle cell crisis or who received a blood transfusion within 3 months were excluded from the study. HbAA siblings of the patients and unaffected age-matched children from the LASUTH pediatric primary care clinic were recruited as control subjects. For a comprehensive assessment of cognitive function, subtests of the Wechsler Intelligence Scale for Children (WISC IV) were administered to assess processing speed (Symbol Search, Coding subtests) and Working Memory (Digit Span, Symbol search subtests) indices. Baseline hemoglobin levels were obtained via a Stat-site hemoglobin analyzer, and oxygen saturation levels were obtained using a pulse oximeter. Baseline demographic data was obtained by surveying the parents/guardians. Lastly, children recruited from the Sickle Cell Foundation TCD clinic (n=24) were stratified by stroke risk levels (standard, conditional, high and indeterminate) based on the TCD velocity values. ResultsA total of 56 children diagnosed with sickle cell disease (M=29, mean age=9.2, SD: 2.76) and 42 unaffected children (M=24, mean age= 9.41, SD: 2.75) participated in this study. We found a higher prevalence of cognitive deficits, especially in areas of processing speed (p=0.013) and short-term auditory memory (p=0.002) in SCD patients as compared to controls. There was also a close association with working memory deficits (p=0.07). Surprisingly, we did not find an association between the cognitive performance of SCD children and their levels of anemia, oxygen levels or body mass index. TCD high risk level was marginally associated with a lower hemoglobin and severe anemia (p=0.05) although there was no significant correlation with working memory and processing speed indices. ConclusionChildren with SCD in Nigeria suffer from cognitive deficits in the areas of memory and attention when evaluated with subtests of the Wechsler Intelligence Scale for Children. We found that, unlike other studies of cognitive function in SCD, our study did not find a correlation between cognitive function and hemoglobin level. It is, therefore, possible that other local environmental or disease-specific factors may be associated with CI in our SCD cohort, or that anemia may affect other cognitive domains not explored by our research. Larger, longitudinal studies should be performed to further elucidate the cognitive function of pediatric SCD patients in Nigeria so that appropriate, locally targeted, preventive interventions can be developed. Disclosures:No relevant conflicts of interest to declare.

Endothelin-1 but not endothelial nitric oxide synthase polymorphisms are implicated in sickle cell disease (P3311)

Abstract Sickle cell disease (SCD) shows marked variability in severity among individuals; this variability probably linked to differential expression of adhesion molecules. Polymorphisms of the endothelial nitric oxide synthase (eNOS) have been implicated in disease severity, potentially delineating vascular complications. There is paucity of information on endothelin-1 (ET-1) diversity and disease severity or ethnic stratification. We examined genomic diversity and estimated haplotype frequency of eNOS and ET-1 polymorphisms in children with SCD. Thirteen SCD children (HbSS) and 176 adult and pediatric controls (HbAA) from Mali were recruited. Genotypic analysis of eNOS variants (T786C, Glu298Asp and intron 4) and ET-1 (G5665T) was carried out with a PCR-RFLP assay. Our results show the frequency distribution and allelic diversity of eNOS and ET-1 variants. Endothelin-1 (G5665T) mutant form was the most frequent, and probably most significant among children with SCD, though the distribution is out of Hardy-Weinberg equilibrium (P=0.0008). eNOS variants showed no difference between SCD and controls. We show that eNOS variants are less frequent, and may have no functional significance in SCD. Additionally, eNOS allele and genotype frequencies are not significantly different in cases and controls. Association between ET-1 and eNOS variants in African versus African American SCD children will be explored and the reason(s) for the HWE deviation will be investigated.

Increased IgE level in Nigerian sickle cell disease children: Implication for severity of allergic reactions

Background: Susceptibility of sickle cell disease subjects to various infectious agents is on the increase, but information relating SCD to allergic condition is scarce. Hence, assessment of immunoglobulin status in SCD children may provide useful information to improve management of SCD children. Objectives: To determine the levels of immunoglobulin classes (IgG, IgA, IgM, and IgE) in Nigerian HbSS children below 5 years of age compared with sex- and age-matched HbAA children. Materials and Methods: Blood samples were collected from a total of 45 children less than 5 years of age who were recruited into the study as follows: 26 HbSS and 19 HbAA subjects for the estimation of serum immunoglobulin levels using enzyme-linked immunosorbent assay (ELISA) techniques and determination of genotype using electrophoresis technique. Results: IgG concentration was nonsignificantly higher (P = 0.997) in HbSS children (1022.56 ± 148.97 ng/ml) compared to HbAA children (933.68 ± 106.10 ng/ml). IgA (P = 0.906) and IgM (P = 0.986) concentrations were nonsignificantly lower in HbSS children (255.07 ± 133.71 ng/ml) compared to HbAA children. IgE was significantly higher (P = 0.000***) in HbSS (108.67 ± 69.22 IU/ml) compared to HbAA (24.51 ± 17.58 IU/ml) children.Conclusion: SCD children in steady state have adequate levels of Ig classes. Non-specific elevation of IgE levels may be a factor of inflammatory response in SCD children, and this may be proposed for reduced allergic reaction among SCD children.